The status of liver function in high-producing dairy cows is critical for normal milk production. The liver performs major integrative roles in carbohydrate, protein, and lipid metabolism of dairy cows.
When dairy cows calve and other ruminants give birth, there is consistently an increase in the amount of lipid stored in the liver during the periparturient period. This lipid level increase is commonly known as "fatty liver" or hepatic lipidosis. Normally, this increased lipid deposition causes no obvious health or milk production problems for a cow. However, under particular circumstances, such as depressed feed intake before calving, infection, or metabolic disease, the deposition of lipid in the cow's liver increases further.
Fatty liver is a major metabolic disease which occurs in up to 50% of all dairy cows. Fatty liver is a "hidden", unobservable disorder that is often is diagnosed only after the cow dies from another disease. The costs associated with fatty liver, therefore, are difficult to estimate. However, the costs of clinical and subclinical ketosis, a complication resulting from fatty liver, have been estimated to be at least $300 million yearly.
Fatty liver has been associated with increased susceptibility to other postpartum diseases and decreased fertility. Cows with severe fatty liver retain viable bacteria in the udder for a much longer time (Hill, A. W. et al., "Invluence of liver fat on experimental Escherichia coli mastitis in periparturient cows", Vet. Rec. 117:549, 1985). Also, cows with fatty livers are leukopenic, with decreases in neutrophils, eosinophils, and lymphocytes (Reid, I. M. et al., "Haematology of sublinical fatty liver in cows", Res, Vet. Sci. 37:63, 1984).
Further, fatty liver leads to the development of other serious diseases and disorders that greatly decrease the profitability of dairying. For instance, especially in cows that are somewhat obese at calving, the major accumulation of lipid associated with fatty liver can result in a severe hepatic lipidosis, which can result in decreased feed intake, downer cow syndrome, delayed estrus, and poor conception rates. Moreover, it has been found that fatty liver seems to be a prerequisite for the development of clinical ketosis (Drackley, J. K. et al., "Metabolic changes in dairy cows with ketonemia in response to feed restriction and dietary 1,3-butanediol", J. Dairy Sci. 75:1622, 1992). Ketosis is characterized by increased concentration of blood ketone bodies, decreased concentrations of blood glucose, anorexia, and decreased milk production. Further, the above-stated problems become amplified because ruminant livers have little capacity to mobilize lipids, such as triacylglycerols, from liver to other tissues.
The pathology of bovine fatty liver has been described (Collins, R. A. and I. M. Reid, "A correlated biochemical and stereological study of periparturient fatty liver in the dairy cow", Res. Vet. Sci., 28:373, 1980). In severe fatty liver, the accumulation of triacylglycerols (TG) is accompanied by disturbances in hepatic structure, including fatty cysts in liver parenchyma, increased cell volume, compression of sinusoids, decreased volume of rough endoplasmic reticulum, and mitochondrial damage. The latter two changes are reflected by decreased concentrations of albumin and increased activities of mitochondrial enzymes released into the blood.
There is therefore a need in the art for a method to prevent the accumulation of lipids and/or a method to stimulate the removal of lipids from the liver of ruminants after calving.
There are two widely accepted functions of glucagon in mammals. These are: 1) to stimulate glucose synthesis and glycogenolysis in liver in order to increase glucose release into the bloodstream; and 2) to stimulate lipolysis in adipose tissue and thereby release nonesterified fatty acids (NEFA) into the bloodstream. Normally, NEFA released from adipose tissue are oxidized for energy by muscle and other tissues such as liver. However, if blood NEFA become too high, some storage of the NEFA can occur in the liver. While humans are able to remove these fatty acids (i.e. lipids) from the liver, ruminants have almost no capacity to remove lipids from the liver.
Based on this conventional understanding of glucagon function, the present inventors originally hypothesized that the administration of glucagon to ruminants would stimulate lipolysis from adipose tissue in lactating cows, which would greatly increase the possibility of those cows accumulating fat in the liver. Thus, the inventors believed that the administration of exogenous glucagon would actually increase the incidence of fatty liver in dairy cows. Surprisingly, the inventors have discovered that the administration of glucagon to cows after calving at the specified low dosages results in a significantly decreased amount of lipid in livers of high-producing lactating cows. Thus, with respect to lipid metabolism, glucagon acts very differently in cattle than it does in humans and other non-ruminant species.
Accordingly, it is a primary objective of the present invention to provide a composition and method for treating fatty liver in high-producing lactating cows and other ruminants using glucagon.
It is a further objective of the present invention to provide a composition and method for treating fatty liver in high-producing lactating ruminants using glucagon which decreases the incidence of metabolic diseases and metabolic imbalances.
It is a further objective of the present invention to provide a composition and method for treating fatty liver in high-producing lactating ruminants using glucagon which allows cows to reach peak milk production sooner.
It is yet a further objective of the present invention to provide a composition and method for treating fatty liver in high-producing lactating ruminants using glucagon which results in increased feed intake during the first few days of lactation.
It is still a further objective of the present invention to provide a composition and method for treating fatty liver in high-producing lactating ruminants using glucagon which is not harmful to the animal and is relatively inexpensive.
The method and means of accomplishing each of the above objectives as well as others will become apparent from the detailed description of the invention which follows hereafter.